DPP-IV is a serine protease widely present in the body, is one of dipeptidyl aminopeptidases capable of hydrolyzing and releasing a N-terminal dipeptide and markedly acts on, in particular, peptides containing proline as the second amino acid from the N-terminal. Therefore, DPP-IV is referred to also as prolyl end peptidase. DPP-IV is known to accept, as substrates, various biological peptides concerned in the endocrine system, the neuroendocrine system, immunological functions and the like. It is known that many physiologically active peptides such as the pancreatic polypeptide family represented by pancreatic polypeptides (PP), neuropeptide Y (NPY) and the like; the glucagon/VIP family represented by vasoactive intestinal polypeptides (VIP), glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptides (GIP), growth hormone-releasing factor (GRF) and the like; and the chemocaine family are substrates for DPP-IV and are subject to the influences of DPP-IV, such as activation/inactivation, metabolism acceleration and the like (non-patent document 1).
DPP-IV severs two amino acids (His-Ala) from the N-terminal of GLP-1. It is known that although the severed peptide binds weekly to a GLP-1 receptor, it has no activating effect on the receptor and acts as an antagonist (non-patent document 2). The metabolism of GLP-1 by DPP-IV in blood is known to be very rapid, and the concentration of active GLP-1 in blood is increased by the inhibition of DPP-IV (non-patent document 3). GLP-1 is a peptide secreted from intestinal tract by the ingestion of sugars and is a main accelerating factor for the glucose-responsive secretion of insulin by pancreas. In addition, GLP-1 is known to have accelerating effect on insulin synthesis in pancreatic β cells and accelerating effect on β cell proliferation. Moreover, it is known that GLP-1 receptors appear also in digestive tracts, liver, muscle, adipose tissue and the like, and it is also known that in these tissues, GLP-1 affects working of the digestive tracts, the secretion of acid in stomach, the synthesis and degradation of glycogen, insulin-dependent glucose uptake, and the like. Accordingly, there is expected the development of a DPP-IV inhibitor effective against type 2 diabetes (non-insulin-dependent diabetes) which brings about effects such as the acceleration of insulin secretion dependent on blood sugar level, the improvement of pancreas function, the improvement of a high postprandial blood sugar level, the improvement of glucose tolerance abnormality, the improvement of insulin resistance, and the like, by increasing the concentration of GLP-1 in blood (non-patent document 4).
Various DPP-IV inhibitors have been reported. For example, patent documents 1 and 2 report that derivatives having an imidazole ring are effective as DPP-IV inhibitors.
Patent document 1: International Publication No. WO 02/068420 pamphlet
Patent document 2: International Publication No. WO 03/104229 pamphlet
Non-patent document 1: J. Langner and S. Ansorge, “Cellular Peptidases in Immune Functions and Disease 2”, Advances in Experimental Medicine and Biology, Vol. 477
Non-patent document 2: L. B. Knudsen et al., European Journal of Pharmacology, Vol. 318, p 429-435, 1996
Non-patent document 3: T. J. Kieffer et al., Endocrinology, Vol. 136, p 3585-3596, 1995
Non-patent document 4: R. A. Pederson et al., Diabetes, Vol. 47, p 1253-1258, 1998